EP1936382A1 - Mikrokanal-chip - Google Patents

Mikrokanal-chip Download PDF

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Publication number
EP1936382A1
EP1936382A1 EP06783269A EP06783269A EP1936382A1 EP 1936382 A1 EP1936382 A1 EP 1936382A1 EP 06783269 A EP06783269 A EP 06783269A EP 06783269 A EP06783269 A EP 06783269A EP 1936382 A1 EP1936382 A1 EP 1936382A1
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EP
European Patent Office
Prior art keywords
capillaries
flow channel
micro flow
capillary
substrate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06783269A
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English (en)
French (fr)
Inventor
Ryuichi Sekizawa
Hideaki Hisamoto
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METABOSCREEN CO Ltd
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METABOSCREEN CO Ltd
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Publication date
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Publication of EP1936382A1 publication Critical patent/EP1936382A1/de
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502707—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the manufacture of the container or its components
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00497—Features relating to the solid phase supports
    • B01J2219/00511—Walls of reactor vessels
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00657—One-dimensional arrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds
    • B01J2219/00725—Peptides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds
    • B01J2219/00729—Peptide nucleic acids [PNA]
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0636—Integrated biosensor, microarrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5025—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures for parallel transport of multiple samples

Definitions

  • the present invention relates to a micro flow channel chip capable of detecting data upon flowing a fluid through multiple micro capillaries and performing prescribed functions with chemical-modification at the capillaries.
  • ⁇ TAS Micro Total Analysis Systems
  • Integrated chips called ⁇ TAS (Micro Total Analysis Systems) are conventionally known as an example of chips having micro flow channels formed on a glass or plastic substrate with the use of micromachining technology to perform necessary biochemical / chemical operation and detection such as reaction and separation using functionalized molecules secured to the flow channel.
  • capillary gel electrophoresis micro chips are known that are used when separating nucleic acid such as fragments of DNA, organic molecule such as amino acid, peptide, and protein, and metal ion in various sizes in micro scales. (see, Patent Reference 1)
  • micro flow channel devices are also conventionally known that have flow channel grooves of a prescribed width and depth formed in a grid pattern on a surface of a substrate, rectangular capillaries laid in some of the flow channel grooves in close contact therewith, and a transparent cover made of transparent glass covering the surface of the substrate of the side of the flow channel grooves.
  • Patent Reference 2 The use of such micro flow channel devices is easy as well as inexpensive, and enables flow channel patterns to be changed easily and freely.
  • Chips such as the capillary gel electrophoresis micro chip and the ⁇ TAS as described above require the micromachining technology such as wet etching and may result in a high cost when a flow channel pattern is once formed and thereafter the formed flow channel pattern is changed, thus lacking flexibility in arrangement of the flow channel pattern.
  • Patent Reference 2 as described above can easily and freely change the flow channel pattern to enable chemical functions to be integrated as necessary, but it is generally expected to greatly shorten a time until collecting detected data by simultaneously measuring multiple items, for example, in virus examination as an application of chemical field and biochemical field.
  • Patent Reference 2 does not specifically disclose the data collection.
  • the present invention is made in consideration of such technical problems as described above, and it is the object of the present invention to provide a micro flow channel chip capable of simultaneously measuring multiple chemical and biochemical functions with the use of a micro flow channel formed on a substrate.
  • the micro flow channel chip of the present invention has multiple grooves formed on a substrate to be connected in parallel or in series and capillaries, each of which is chemically-modified in a manner different from each other, laid respectively in the multiple grooves to collect detected data upon a fluid being supplied to the thus laid multiple capillaries.
  • the micro flow channel chip of the present invention has the capillaries laid in the preformed grooves on the substrate to result in an adaptive structure capable of replacing the capillaries to cope with a situation such as where examination items are replaced. Furthermore, it is supposed that each of the capillaries is chemically-modified in a manner different from each other, and the micro flow channel chip can simultaneously measure multiple chemical and biochemical functions without interference between each of the capillaries.
  • micro flow channel chip of the present invention "chemically-modified in a different manner" as used herein has a broad meaning, and realizes chemical operations such as mixing, reaction, and separation in broad fields such as biochemical field, pharmaceutical field, environmental measurement field, and molecular biological field without being limited to chemical field.
  • the micro flow channel chip of the present invention enables simultaneous detection and simultaneous quantity detection in antigen-antibody reaction by arranging capillaries side by side having various types of animal immunoglobulin G (IgG) antibodies secured thereto.
  • IgG animal immunoglobulin G
  • ELISA Immuno-Assay or Enzyme-Linked Immuno Sorbent Assay
  • ELISA is a method for determining the concentration of a substance to be examined (examined substance) by simultaneously applying the examined substance and an enzyme-labeled antigen to a micro plate having an antibody (protein) secured thereto specifically reacting with the examined substance to cause the examined substance and an enzyme-labeled antigen to react therewith and measuring with absorptiometric method the enzyme activity of an enzyme-labeled substance bonded with the plate, and is a method for quantity detection by analyzing simultaneously or consecutively a light transmitted through or reflected by the multiple capillaries arranged side by side.
  • the micro flow channel chip of the present invention can be configured to obtain data via image processing using a thermal lens microscope, a fluorescent microscope,
  • micro flow channel chip of the present invention multiple chemical and biochemical functions can be measured simultaneously with the use of the micro flow channel formed on the substrate, and thus, a work originally requiring many chemical operations such as virus identification and the like can be performed in a very short time, and the work can be proceeded with very economically due to the structure of the chip capable of being mass-produced.
  • Fig. 1 is a cross-sectional diagram of an essential portion of a micro flow channel chip according to an embodiment of the present invention.
  • the micro flow channel chip uses a substrate 10 made of polydimethylsiloxane (PDMS), a polymeric material substrate, and has capillaries 21 to 24 in a rectangular pillar form respectively laid in four grooves 13 to 16 formed on a surface 11 of the substrate 10 as shown in Fig. 1 .
  • One end of each of the four capillaries 21 to 24 is formed facing a flow channel 12.
  • PDMS polydimethylsiloxane
  • the substrate 10 may have grooves arranged in a grid pattern as disclosed in Patent Reference 2 described above, or alternatively, as many grooves as the capillaries may be formed on the substrate 10 to accommodate many types of the capillaries laid in the grooves.
  • the substrate 10 is tabular in the embodiment, the substrate 10 may be in other forms capable of holding the capillaries.
  • the substrate 10 made of polymeric material is flexible to a certain extent. Accordingly, the capillary can be inserted into the groove by expanding to some extent the groove accommodating the capillary inserted therein when the capillary is to be laid in the capillary, and the capillary can be held in the groove without any gap after the capillary is laid in the groove.
  • the substrate can be comprised of silicone rubber such as polydimethylsiloxane (PDMS) and polydiphenylsiloxane, glass, or other polymeric material.
  • the groove may have the dimension of, for example, approximately 300 micron in width and 300 micron in depth to have a cross section in a form of a very small square, and accordingly, the capillary has a side surface and a bottom surface of the same dimension due to the square cross section, thus capable of being laid in the groove without a problem of the direction as to which is the side surface and which is the bottom surface.
  • the flow channel in the capillary is 100 micron by 100 micron
  • the outer diameter of the capillary is 300 micron by 300 micron to be the same size as the groove.
  • the four capillaries 21 to 24 in a rectangular pillar form laid in the grooves 13 to 16 as described above are flexible micro rectangular pillar members made of silica glass chemically-modified in different manners to have different chemical functions, and the four capillaries 21 to 24 have flow channels 25 to 28 in the rectangular pillar form inside thereof. Substances causing reaction such as antibody and enzyme are secured to the interior wall of the flow channels 25 to 28.
  • a reagent for AIDS examination is secured to the first capillary
  • a reagent for hepatitis examination is secured to the next capillary
  • other capillaries can be used for, e.g., cancer and sexual disease examinations.
  • the micro flow channel chip of the present invention has the same blood flow through four different capillaries as described above, and thus makes independent examinations for each of the four diseases unnecessary, that is, the examination should be performed for only once to determine as to whether positive or negative, and thus, the micro flow channel chip of the present invention is very effective especially in cases where an urgent treatment is required.
  • the capillaries can be a combination for simultaneously examining multiple types of hepatitis, and in cases where various types of diseases exist such as virus, the capillaries can be a combination for examining the diseases to determine at a time as to which type of the diseases.
  • each of the capillaries can be arranged to simultaneously perform examinations of, for example, hyperlipidemia, diabetes, and fatty liver.
  • Body fluids such as urine and blood can be used in the multiple capillaries to simultaneously perform multiple examinations such as examinations for bladder cancer, prostate cancer, uterine cancer, or doping test.
  • the micro flow channel chip of the present invention can be applied for identification and quantity detection of cytokine, hormone, environmental hormone, and the like.
  • the micro flow channel chip of the present invention can be used to detect agrichemical and bacillus in foods and to detect the quantity thereof, and can identify toxic substances.
  • the micro flow channel chip of the present invention can realize component analysis of various molecules in a cell such as various proteins, nucleic acid, and physiologically active substance, and also can realize detecting the activity of various enzymes in a cell and detecting the quantity thereof.
  • the capillaries can be a combination for detecting the quantity of multiple metal ions included in mineral water such as hot spring.
  • the micro flow channel chip of the present invention can perform detection according to ELISA method as hereinafter described, and has a structure in which an antibody is secured to the inner surface of the four capillaries 21 to 24 in the rectangular pillar form and an antigen solution is supplied to cause antigen-antibody reaction to realize quantity detection, thus being especially effective in cases of disease examination and virus examination.
  • Fig. 2 and Fig. 3 are a plan diagram and a cross-sectional diagram, and the capillaries 21 and 22 have the flow channel 25 and 26 in the rectangular pillar form inside thereof for different chemical modifications.
  • the capillaries 21 and 22 are made of silica glass in the present embodiment, but can be made of other glass and synthetic resin material.
  • the inner wall is formed to have a cavity in the rectangular pillar from, but a cavity may be in a cylinder form or other forms.
  • the inner wall of the capillaries may be chemically-modified to be made a chemically-modified portion for ion-sensing, molecular sensing, pH sensing, filtering, concentration, antigen-antibody reaction, enzyme reaction, catalytic reaction, immune reaction, oil-water separation, or flow control.
  • many types of chemical functions such as molecular recognition, reaction, separation, and detection can be freely integrated into a piece of the micro flow channel tip.
  • the capillaries are, for example, made of glass or plastic. As an example of the former, Square Flexible Fused Silica Capillary Tubing sold by Polymicro Technologies, LLC made of silica glass and having a square outer cross section is used.
  • the grooves having the square cross section and having the same size as the outer form of the capillaries are arranged on the substrate, and a prescribed number of the capillaries cut to a prescribed length are laid in some portion of the grooves, and thus, the micro flow channel is made into a desired pattern easily and freely.
  • the capillaries of the micro flow channel chip of the present invention has at least one transparent surface thereof.
  • the transparent surface proceedings and results of chemical operation at the micro flow channels can be easily seen, and the transparent surface is preferable for quantity detection according to ELISA method as hereinafter described.
  • the cross-sectional form of the inner wall of the capillary is not limited to a specific form, but is preferred to be a substantially rectangular form in consideration of ensuring chemical functions as described above.
  • Fig. 4 and Fig. 5 are diagrams showing a relationship between the substrate 10 and a groove 19 being the flow channel, and Fig. 4 is a plan view omitting some portion whereas Fig. 5 is a perspective diagram.
  • the substrate 10 made of polymeric material such as glass and polydimethylsiloxane (PDMS) has the groove 19 formed lengthwise and crosswise in a grid pattern and a surface surrounded by the groove 19 in a square matrix form protruding from a groove bottom portion.
  • PDMS polydimethylsiloxane
  • the groove 19 is formed lengthwise and crosswise in the grid pattern, the distance between crossings on one of the grooves in a crosswise direction and the distance between crossings on one of the grooves in a lengthwise direction are substantially constant, but the distance between crossings in the crosswise direction and the lengthwise direction can be changed.
  • the four types of the capillaries 21 to 24 are prepared as shown in Fig. 6 , and each of the four types of the capillaries 21 to 24 is laid in a portion of the groove in the lengthwise direction to be parallel with each other.
  • Dummy capillaries 18 for closing the flow channel are laid in portions of the groove that need to be blocked.
  • a prescribed number of the flexible rectangular capillaries are cut into a prescribed length and has the flow channels thereof filled with PDMS and the like to be used as the dummy capillaries 18.
  • the dummy capillaries as described above laid in the flow channels block a specific portion of the low channels, and thus, the flow channel of the micro flow channel chip is made into a prescribed pattern.
  • the four types of the capillaries 21 to 24 are arranged in parallel in the crosswise direction, and a fluid introduced from an inlet side of the flow channel 12a made of the groove flows through each of the capillaries 21 to 24 and is discharged via an exit side of the flow channel 12b.
  • the flow channel 12a can be opened at two locations or more to introduce the fluids.
  • a prescribed cover may be attached on the substrate after the capillaries are laid in the grooves.
  • a transparent sheet or transparent film made of glass or plastic can be employed as the cover, and an internal state of the micro flow channel can be observed from outside in such cases.
  • a substance functioning as the reagent is dissolved in a methanol (MeOH) solution, and this solution is injected into the flow channel 31 of the capillary 30 having the square cross section. After air is filled, the solution injected into the flow channel 31 having the square cross section holds air in the middle thereof, and upon 24 hours of air-drying, the solution is secured to the inner wall of the capillary 30.
  • MeOH methanol
  • a fluorescence detection trypsin substrate (benzoyl-L-arginine 4-methyl-coumaryl-7-amide;Bz-Arg-MCA) or a pH detection reagent (fluorescein) and a polyethylene glycol are dissolved in the methanol (MeOH) solution, and the solution is introduced into the capillary 30 of the flow channel 31, so that the solution can be secured to the inner wall of the capillary 30 after 24 hours of air-drying.
  • the antibody is preferred to be previously secured to the inner wall of the flow channel 31 having the square cross section, and diagnosis according to ELISA method can be achieved by successively supplying an antigen, an enzyme-labeled antibody, and a substrate as hereinafter described.
  • Fig. 9 shows states of the capillary 32 during detection operation.
  • a film made by securing a reagent is formed on the inner wall of the flow channel 33 having the square cross section according to steps such as the steps described in Fig. 8 , and especially, components of the reagent exist at four corner portions of the capillary 32 just like a residual after drying.
  • a solution to be a sample is introduced to the capillary 32 by capillary action.
  • the sample is introduced into the flow channel 33 of the capillary 32 having the square cross section to allow the reagent to be released from the film having the reagent secured therein, thus resulting in a phenomenon of a prescribed reaction, for example, coloring, fluorescence, and the like.
  • Fig. 9 shows an example in which the reagent is released from the film formed on the inner wall, and there are examples of a coloring reaction caused by chemical reaction and a coloring reaction caused by the substrate released from the inner wall of the flow channel 33 of the capillary 3 having the square cross section such as enzyme reaction.
  • a coloring reaction caused by chemical reaction and a coloring reaction caused by the substrate released from the inner wall of the flow channel 33 of the capillary 3 having the square cross section
  • enzyme reaction the capillary releasing the substrate and the enzyme itself can be employed.
  • micro flow channel chip of the present invention is hereinafter further described in detail based on the experimental example performed by the inventor of the present invention.
  • Fig. 10 shows a model for a measuring method according to ELISA method, and is an example in which enzyme reaction was analyzed with a human IgG reaction system.
  • the grooves are formed in the lattice form on the substrate 40, and the five rectangular capillaries 43a to 43d and 43e are laid in parallel thereon.
  • the dummy capillaries 42 are attached on the grooves that are not used as the flow channels.
  • a bulb capillary 41 made of poly (N-isopropyl acrylic amide), a temperature sensitive polymer, is formed at the inlet of the five parallel rectangular capillaries 43a to 43d and 43e.
  • the bulb capillary 42 can control opening and closing of the flow channel depending on temperature.
  • the five rectangular capillaries 43a to 43d and 43e having a human IgG antibody secured thereto were laid in parallel to make the tip.
  • an antigen solution was introduced from an inlet 44 to fill each of the rectangular capillaries 43a to 43d and 43e themselves while the antigen solution was allowed to be discharged via an outlet 45, and subsequently, the bulb capillary 41 was closed to allow the reaction to proceed.
  • an enzyme-labeled antibody solution (Anti-IgG-HRP) and a substrate solution (TOSS, 4-AA) generating red pigments were subjected to reaction and observed with a thermal lens microscope (excitation wavelength 532nm, detected wavelength 658nm).
  • the enzyme reaction proceeded to caused a thermal lens microscope signal strength to reach a constant value in approximately 60 seconds. Subsequently, a time to adequately complete the antigen-antibody reaction in this system was surveyed. Consequently, where the antigen-antibody reaction was performed for 12 minutes or more, the thermal lens signal strength became constant. Therefore, a total reaction time in the antibody secured capillary is approximately 30 minutes, and accordingly, it turns out that a rapid immunoassay can be performed.
  • Fig. 11 shows signal strengths of five capillaries when the micro flow channel chip of Fig. 10 is used. Approximately 19 % deviation was observed among the signal strengths, but it is proved that useful data can be obtained.
  • Fig. 12 is a diagram showing an experimental example of a model using a fluorescein releasing capillary.
  • the central groove on the substrate 50 is structured to be provided with a sample solution of which pH value should be measured, and central-side ends of fluorescein releasing capillaries 51 and 52 arranged on both sides of the central groove are open to allow the sample solution to be introduced via the openings into the fluorescein releasing capillaries 51 and 52.
  • FIG. 12 shows actual fluorescence over time
  • Fig. 13 shows a relationship between a fluorescence strength F and a pH value.
  • Figs. 14 and 15 are diagrams showing that a substrate releasing capillary capable of being used for measuring enzyme activity functions as the micro flow channel chip, and Fig. 14 is data of enzyme activity measured by the substrate releasing capillary according to the experimental example of the present invention, whereas Fig. 15 is data measured by the assay using a microtiter plate as a comparative example.
  • signals are weaker, but regarding the trypsin concentration, the obtained data is adequately of the same grade as the assay using the general microtiter plate with respect to reaction speed and reaction temperature, and the assay using the substrate releasing capillary can be made smaller than the assay using the microtiter plate to enable operations to proceed very inexpensively.
  • Figs. 16 and 17 are fluorescent microscope pictures respectively of enzyme activity assay and pH sensing, and the enzyme activity assay uses the trypsin substrate releasing capillary, whereas the pH sensing is an example of a model using the fluorescein releasing capillary. In both cases, fluorescence is observed in a width of approximately 100 micron that is the same width as the width of the inner wall of the flow channel of the substantially rectangular capillary, and thus, an effective measuring is realized.
  • Fig. 18 is a diagram in which calibration curves for the antigen concentration are drawn with respect to not only the human IgG but also a chicken IgG and a goat IgG with the use of the model shown in Fig. 10 .
  • the antigen-antibody reactions are caused in the same manner as the reaction system of the human IgG as described above, and it is proved that the same result of measured quantity is obtained. Accordingly, the micro flow channel chip of the present invention arranging different types of capillaries even for different enzyme reactions and antigen-antibody reactions to perform measurement simultaneously is proved to be effective.
  • a liquid supplied to each of the capillaries has only to have something in common, and each of the capillaries may be connected with each other in series.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
EP06783269A 2005-09-13 2006-09-11 Mikrokanal-chip Withdrawn EP1936382A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2005007535U JP3116709U (ja) 2005-09-13 2005-09-13 微小流路チップ
PCT/JP2006/317996 WO2007032316A1 (ja) 2005-09-13 2006-09-11 微小流路チップ

Publications (1)

Publication Number Publication Date
EP1936382A1 true EP1936382A1 (de) 2008-06-25

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EP06783269A Withdrawn EP1936382A1 (de) 2005-09-13 2006-09-11 Mikrokanal-chip

Country Status (5)

Country Link
US (1) US20090215158A1 (de)
EP (1) EP1936382A1 (de)
JP (1) JP3116709U (de)
CN (1) CN101263392B (de)
WO (1) WO2007032316A1 (de)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010104497A1 (en) 2009-03-07 2010-09-16 Hewlett-Packard Development Company, L.P. Analyzer and method for sensing using the same
US20120301903A1 (en) * 2009-11-23 2012-11-29 Putnam Martin A Microfluidic Devices and Methods of Manufacture and Use
WO2013133899A1 (en) * 2012-03-08 2013-09-12 Cyvek, Inc Microfluidic assay systems employing micro-particles and methods of manufacture
US9229001B2 (en) 2009-11-23 2016-01-05 Cyvek, Inc. Method and apparatus for performing assays
US9500645B2 (en) 2009-11-23 2016-11-22 Cyvek, Inc. Micro-tube particles for microfluidic assays and methods of manufacture
US9651568B2 (en) 2009-11-23 2017-05-16 Cyvek, Inc. Methods and systems for epi-fluorescent monitoring and scanning for microfluidic assays
US9700889B2 (en) 2009-11-23 2017-07-11 Cyvek, Inc. Methods and systems for manufacture of microarray assay systems, conducting microfluidic assays, and monitoring and scanning to obtain microfluidic assay results
US9759718B2 (en) 2009-11-23 2017-09-12 Cyvek, Inc. PDMS membrane-confined nucleic acid and antibody/antigen-functionalized microlength tube capture elements, and systems employing them, and methods of their use
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CN101263392A (zh) 2008-09-10

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